Process for preparing 1-methoxymethyl-5,5-diphenylbarbituric acid

ABSTRACT

The present invention provides a novel process for preparing 1-methoxymethyl-5,5-diphenylbarbituric acid. In particular, the present invention provides a process for preparing 1-methoxymethyl-5,5-diphenylbarbituric acid by reacting 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid with a Lewis acid to selectively remove one methoxymethyl group from 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 60/584,955, filed Jul. 2, 2004, thedisclosure of which is incorporated by reference in its entirety herein.

FIELD OF THE INVENTION

The present invention relates to a process for preparing1-methoxymethyl-5,5-diphenylbarbituric acid. In particular, the presentinvention relates to a process for preparing1-methoxymethyl-5,5-diphenylbarbituric acid by reacting1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid with a Lewis acid toselectively remove one methoxymethyl group from1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid.

BACKGROUND OF THE INVENTION

Barbituric acid (CAS # 67-52-7, CAS name:2,4,6(1H,3H,5H)-pyrimidinetrione) and its derivatives possess usefulpharmacological properties, including anti-convulsant, anti-anxiety andmuscle relaxant activities. In addition, many barbituric acidderivatives further possess sedative and/or hypnotic activities, whichmakes the compounds disadvantageous for patients who wish to maintainmental acuity.

1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid is a barbituric acidderivative that possesses anti-convulsant, anti-anxiety and musclerelaxant activities, but does not possess major sedative or hypnoticactivities. As such, the compound is considered to be a promisingcandidate for patients who wish to maintain mental acuity.

U.S. Pat. No. 4,628,056 (the '056 patent) discloses a process forpreparing 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid, wherein5,5-diphenylbarbituric acid is reacted with sodium hydride andchloromethyl methyl ether. The reaction results in the addition of twomethoxymethyl groups to the 5,5-diphenylbarbituric acid to form1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid.

1-methoxymethyl-5,5-diphenylbarbituric acid is an analog of1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid that is believed topossess a similar spectrum of activity. Thus,1-methoxymethyl-5,5-diphenylbarbituric acid is believed to possessanti-convulsant, anti-anxiety and muscle relaxant activities, withoutpossessing major sedative or hypnotic activities, and is similarlyconsidered to be a promising candidate for patients who wish to maintainmental acuity.

U.S. Pat No. 6,093,820 discloses a two step process for preparing1-methoxymethyl-5,5-diphenylbarbituric acid, in which5,5-diphenylbarbituric acid is first reacted with excess sodium hydride,and then reacted with methoxymethyl methanesulfonate. As in the '056patent process for preparing 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid, the '820 patent process utilizes5,5-diphenylbarbituric acid as a starting material, but only onemethoxymethyl group is added, not two. The '820 patent further disclosesa pharmaceutical formulation of 1-methoxymethyl-5,5-diphenylbarbituricacid for treating convulsions, seizures, muscle stiffness, nervousstrain and anxiety.

There is a continuing need for a process for preparing1-methoxymethyl-5,5-diphenylbarbituric acid.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing1-methoxymethyl-5,5-diphenylbarbituric acid comprising the steps of:

-   -   (a) reacting 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid        with about 0.2 to about 2 equivalents of a Lewis acid selected        from the group consisting of aluminum chloride, boron        trifluoride diethyl etherate, boron tribromide, and mixtures        thereof, at a temperature of about 70° C. to about 130° C. for        about one to about five hours to form        1-methoxymethyl-5,5-diphenylbarbituric acid; and    -   (b) isolating the 1-methoxymethyl-5,5-diphenylbarbituric acid.

Preferably, the Lewis acid is aluminum chloride.

Preferably, step (a) is performed in an aromatic solvent. Morepreferably, the aromatic solvent is selected from the group consistingof chlorobenzene, bromobenzene, nitrobenzene, dichlorobenzene,o-nitrotoluene, anisole, and mixtures thereof. More preferably, thearomatic solvent is chlorobenzene.

Preferably, the 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid isreacted with about 0.4 to about 1 equivalent of the Lewis acid. Morepreferably, the 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid isreacted with about 0.6 equivalent of the Lewis acid.

Preferably, step (a) is performed at a temperature of about 80° C. toabout 120° C. More preferably, step (a) is performed at a temperature ofabout 90° C. to about 110° C.

Preferably, step (a) is performed for about two hours.

Preferably, the 1-methoxymethyl-5,5-diphenylbarbituric acid is producedas a single batch of at least about 500 grams.

Preferably, step (b) further comprises the steps of:

-   -   a′) extracting the 1-methoxymethyl-5,5-diphenylbarbituric acid        into a basic aqueous solution;    -   b′) acidifying the basic aqueous solution to precipitate the        extracted 1-methoxymethyl-5,5-diphenylbarbituric acid; and    -   c′) collecting the precipitated 1        -methoxymethyl-5,5-diphenylbarbituric acid.

Preferably, the basic aqueous solution is a sodium hydroxide solution.

Preferably, when step (a) is performed in an aromatic solvent, step (b)further comprises the steps of:

-   -   a′) combining the aromatic solvent with water to form a        precipitate;    -   b′) separating the aromatic solvent from the water and the        precipitate;    -   c′) extracting the 1-methoxymethyl-5,5-diphenylbarbituric acid        from the aromatic solvent into a basic aqueous solution;    -   d′) acidifying the basic aqueous solution to precipitate the        extracted 1-methoxymethyl-5,5-diphenylbarbituric acid; and    -   e′) collecting the precipitated        1-methoxymethyl-5,5-diphenylbarbituric acid.

Preferably, the basic aqueous solution is a sodium hydroxide solution.

Preferably, when step (a) is performed in an aromatic solvent, step (b)further comprises the steps of:

-   -   a′) combining the aromatic solvent with an acidic aqueous        solution to form a precipitate;    -   b′) separating the aromatic solvent from the acidic aqueous        solution and the precipitate;    -   c′) evaporating the aromatic solvent to form a concentrate;    -   d′) dissolving the concentrate in a non-aromatic organic        solvent;    -   e′) extracting the 1-methoxymethyl-5,5-diphenylbarbituric acid        from the non-aromatic organic solvent into a basic aqueous        solution;    -   f′) acidifying the basic aqueous solution to precipitate the        extracted 1 -methoxymethyl-5,5-diphenylbarbituric acid; and    -   g′) collecting the precipitated        1-methoxymethyl-5,5-diphenylbarbituric acid.

Preferably, the basic aqueous solution is a sodium hydroxide solution.

Preferably, the non-aromatic organic solvent is selected from the groupconsisting of ethyl acetate, diethyl ether, methylene chloride, andmixtures thereof. More preferably, the non-aromatic organic solvent isethyl acetate.

Preferably, the process further comprises the step of purifying theisolated 1-methoxymethyl-5,5-diphenylbarbituric acid. Preferably, thepurifying step is performed by crystallization from a solvent.Preferably, the solvent is at least one solvent selected from the groupconsisting of toluene, tert-butyl methyl ether, ethanol, methanol, watermixed with ethanol, and water mixed with methanol.

Preferably, the 1-methoxymethyl-5,5-diphenylbarbituric acid has a puritygreater than 99%.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms are defined: “Lewis acid” refers toany species that can accept a pair of electrons and form a coordinatecovalent bond; “equivalent” refers to the relative molar quantity (i.e.,mole/mole ratio) of one reagent in a chemical reaction with reference toanother; “aromatic solvent” refers to a solvent having a molecularstructure that includes a phenyl ring; “non-aromatic organic solvent”refers to an organic solvent having a molecular structure that does notinclude a phenyl ring; “isolating 1-methoxymethyl-5,5-diphenylbarbituricacid” refers to separating 1-methoxymethyl-5,5-diphenylbarbituric acidinto a composition of matter, wherein the fraction (by weight) of the1-methoxymethyl-5,5-diphenylbarbituric acid in the composition isgreater than the fraction (by weight) of each other component of thecomposition, taken individually; “basic aqueous solution” refers to anaqueous solution, optionally including a water miscible organic solvent(e.g., methanol), having a pH greater than 7; an “acidic aqueoussolution” refers to an aqueous solution, optionally including a watermiscible organic solvent (e.g., methanol), having a pH less than 7;“commercial scale” refers to a batch size of at least about 100 grams;“batch” refers to the quantity of a product formed during a singlechemical process.

The present invention provides a process for preparing1-methoxymethyl-5,5-diphenylbarbituric acid comprising the steps of:

-   -   (a) reacting 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid        with about 0.2 to about 2 equivalents of a Lewis acid selected        from the group consisting of aluminum chloride, boron        trifluoride diethyl etherate, boron tribromide, and mixtures        thereof, at a temperature of about 70° C. to about 130° C. for        about one to about five hours to form        1-methoxymethyl-5,5-diphenylbarbituric acid; and    -   (b) isolating the 1-methoxymethyl-5,5-diphenylbarbituric acid.

Suitable processes for preparing1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid are known in the art.For example, 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid may beprepared by the following two steps: (1) reacting dimethoxymethane withacetyl methanesulfonate; and (2) reacting the resulting methoxymethylmethanesulfonate with 5,5-diphenylbarbituric acid in the presence ofN,N-diisopropylethylamine. This two-step process is described in detailin U.S. Pat. No. 6,093,820, which is incorporated herein by reference inits entirety.

The 5,5-diphenylbarbituric acid used in step (2) of the above processmay be prepared by reacting benzene with alloxan as described by S. M.McElvain in “5,5-diphenylbarbituric acid,” J. Am. Chem. Soc. 1935, 57,1303-1304. See also Barnes, H. M. and McElvain, S. M., “Furtherobservations on the condensation of benzene with alloxan,” J. Am. Chem.Soc. 1937, 59, 2348-2351. The McElvain and Barnes and McElvain articlesare incorporated herein by reference in their entireties.

The 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid used in step (a)of the present process may be crystalline, amorphous, semisolid, syrup,a mixture thereof, or the like. Crystalline1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid may includepolymorphs, solvates, clathrates, and the like, and mixtures thereof.

Optionally, the 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid usedin step (a) of the present invention may be crude. Crude1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid refers to1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid that is synthesizedby a chemical reaction and isolated from the reaction mixture, but notfurther purified.

The Lewis acid is selected from the group consisting of aluminumchloride, boron trifluoride diethyl etherate, boron tribromide, andmixtures thereof. Preferably, the Lewis acid is aluminum chloride.

Optionally, the reacting step (a) may be performed in a solvent.Suitable solvents include, but are not limited to, aromatic solvents.Suitable aromatic solvents include, but are not limited to,chlorobenzene, bromobenzene, nitrobenzene, dichlorobenzene,o-nitrotoluene, anisole, mixtures thereof, and the like. Preferably, thearomatic solvent is chlorobenzene.

The reaction conditions (e.g., reagent ratio, reaction temperature,reaction time) in step (a) may be suitably controlled to ensure that theLewis acid selectively removes one methoxymethyl group from1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid to form1-methoxymethyl-5,5-diphenylbarbituric acid. With reference to thereagent ratio, reacting step (a) is performed using about 0.2 to about 2equivalents of the Lewis acid (i.e., the mole/mole ratio of the Lewisacid to the 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid is about0.2 to about 2). Preferably, step (a) is performed using about 0.4 toabout 1 equivalent of the Lewis acid. More preferably, step (a) isperformed using about 0.6 equivalent of the Lewis acid.

With reference to reaction temperature, step (a) is performed at atemperature of about 70° C. to about 130° C. Preferably, step (a) isperformed at a temperature of about 80° C. to about 120° C. Morepreferably, step (a) is performed at a temperature of about 90° C. toabout 110° C.

With reference to reaction time, step (a) is performed for about one (1)to about five (5) hours. Preferably, step (a) is performed for about two(2) hours.

In a preferred embodiment, the process of the present invention isperformed at a commercial scale. Preferably, the1-methoxymethyl-5,5-diphenylbarbituric acid is produced as a singlebatch of at least about 100 grams. More preferably, the1-methoxymethyl-5,5-diphenylbarbituric acid is produced as a singlebatch of at least about 500 grams. More preferably, the1-methoxymethyl-5,5-diphenylbarbituric acid is produced as a singlebatch of at least about one (1) kilogram.

In accordance with the present invention, the prepared1-methoxymethyl-5,5-diphenylbarbituric acid may be isolated in step (b)using standard methods. Suitable isolation methods include, but are notlimited to, removing the solvent from the reaction mixture. Suitableisolation methods further include, but are not limited to, the followingthree embodiments.

In a first embodiment, the isolating step (b) may further comprise thesteps of:

-   -   a′) extracting the l-methoxymethyl-5,5-diphenylbarbituric acid        into a basic aqueous solution;    -   b′) acidifying the basic aqueous solution to precipitate the        extracted 1-methoxymethyl-5,5-diphenylbarbituric acid; and    -   c′) collecting the precipitated        1-methoxymethyl-5,5-diphenylbarbituric acid.

In a second embodiment, the reacting step (a) may be performed in anaromatic solvent, and the isolating step (b) may further comprise thesteps of:

-   -   a′) combining the aromatic solvent with water to form a        precipitate;    -   b′) separating the aromatic solvent from the water and the        precipitate;    -   c′) extracting the 1-methoxymethyl-5,5-diphenylbarbituric acid        from the aromatic solvent into a basic aqueous solution;    -   d′) acidifying the basic aqueous solution to precipitate the        extracted 1-methoxymethyl-5,5-diphenylbarbituric acid; and    -   e′) collecting the precipitated        1-methoxymethyl-5,5-diphenylbarbituric acid

In a third embodiment, the reacting step (a) may be performed in anaromatic solvent, and the isolating step (b) may further comprise thesteps of:

-   -   a′) combining the aromatic solvent with an acidic aqueous        solution to form a precipitate;    -   b′) separating the aromatic solvent from the acidic aqueous        solution and the precipitate;    -   c′) evaporating the aromatic solvent to form a concentrate;    -   d′) dissolving the concentrate in a non-aromatic organic        solvent;    -   e′) extracting the 1-methoxymethyl-5,5-diphenylbarbituric acid        from the non-aromatic organic solvent into a basic aqueous        solution;    -   f′) acidifying the basic aqueous solution to precipitate the        extracted 1-methoxymethyl-5,5-diphenylbarbituric acid; and    -   g′) collecting the precipitated        1-methoxymethyl-5,5-diphenylbarbituric acid.

The second and third of the above-described embodiments each begins withtwo steps: a combining step, followed by a separating step.

With reference to the combining step, in the second embodiment thecombining step a′) is performed by adding water to the aromatic solventin a quantity sufficient to cause a precipitate to form. Preferably, thecombining step is performed using a vol/vol ratio of the water to thearomatic solvent of about 0.1:1 to about 2:1. More preferably, thecombining step is performed using a vol/vol ratio of the water to thearomatic solvent of about 0.3:1 to about 1:1. More preferably, thecombining step is performed using a vol/vol ratio of the water to thearomatic solvent of about 0.5:1.

In the third embodiment, the combining step a′) is performed by addingan acidic aqueous solution to the aromatic solvent in a quantitysufficient to cause a precipitate to form. The acidic aqueous solutionmay be prepared using standard methods. Suitable methods include, butare not limited to, dissolving an acid in water, and dissolving an acidin a mixture of water and one or more water miscible organic solvents.Suitable acids include, but are not limited to, mineral acids. Suitablewater miscible organic solvents include, but are not limited to,methanol.

With reference to the separating step, in the second embodiment theseparating step b′) is performed by removing the precipitate and thewater from the aromatic solvent. In the third embodiment, the separatingstep b′) is performed by removing the precipitate and the acidic aqueoussolution from the aromatic solvent. Suitable methods for removing theprecipitate from the aromatic solvent include, but are not limited to,filtering, centrifuging, and decanting. Suitable methods for removingthe water or the acidic aqueous solution from the aromatic solventinclude, but are not limited to, using a separatory funnel.

The third of the above-described embodiments includes two intermediatesteps: an evaporating step; followed by a dissolving step.

The evaporating step c′) is performed by evaporating a portion of theseparated aromatic solvent to form a concentrate, which contains1-methoxymethyl-5,5-diphenylbarbituric acid. The evaporating step may beperformed using any suitable method. Suitable methods include, but arenot limited to, heating the aromatic solvent to an elevated temperature,and exposing the aromatic solvent to a reduced pressure. Preferably, theevaporating step is performed until substantially all of the aromaticsolvent is evaporated.

The dissolving step d′) is performed by dissolving the concentrate in anon-aromatic organic solvent. Suitable non-aromatic organic solventsinclude, but are not limited to, ethyl acetate, diethyl ether, methylenechloride, and mixtures thereof. Preferably, the non-aromatic organicsolvent is ethyl acetate.

Each of the above-described embodiments concludes with three steps: anextracting step; followed by an acidifying step; and then a collectingstep.

In each embodiment, the extracting step a′), c′), or e′) is performed byextracting the 1-methoxymethyl-5,5-diphenylbarbituric acid that isprepared in reacting step (a) from an organic solvent into a basicaqueous solution. Suitable organic solvents for the extracting stepinclude, but are not limited to, aromatic solvents and non-aromaticorganic solvents. Suitable aromatic solvents include, but are notlimited to, chlorobenzene, bromobenzene, nitrobenzene, dichlorobenzene,o-nitrotoluene, anisole, and the like. Suitable non-aromatic organicsolvents include, but are not limited to, ethyl acetate, methylenechloride, diethyl ether, and the like. Optionally, the organic solventmay include the reaction solvent.

The basic aqueous solution used in the extracting step may be preparedusing any suitable method. Suitable methods include, but are not limitedto, dissolving a base in water, and dissolving a base in a mixture ofwater and one or more water miscible organic solvents. Suitable basesinclude, but are not limited to, sodium hydroxide, potassium hydroxide,sodium carbonate, and potassium carbonate. Preferably, the base issodium hydroxide. Suitable water miscible organic solvents include, butare not limited to, methanol.

In each embodiment, the acidifying step b′), d′), or f′) is performed byreducing the pH of the basic aqueous solution enough to cause the1-methoxymethyl-5,5-diphenylbarbituric acid to precipitate fromsolution. Suitable methods for performing the acidifying step include,but are not limited to, adding acid to the basic aqueous solution.Suitable acids include, but are not limited to, mineral acids. Mineralacids include, but are not limited to, hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid, mixtures thereof, and the like.Preferably, the pH of the solution is reduced to about 5 or lower. Morepreferably, the pH of the solution is reduced to about 4 or lower.

In each embodiment, the collecting step c′), e′), or g′) may beperformed using any suitable method. Suitable methods for collecting theprecipitated 1-methoxymethyl-5,5-diphenylbarbituric acid include, butare not limited to, filtering, centrifuging, and decanting.

The isolated 1-methoxymethyl-5,5-diphenylbarbituric acid may be furtherpurified. Suitable purification methods include, but are not limited to,high performance liquid chromatography (HPLC) and crystallization.Preferably, the isolated 1-methoxymethyl-5,5-diphenylbarbituric acid ispurified by crystallization from a solvent. Suitable crystallizationsolvents include, but are not limited to, toluene, tert-butyl methylether, ethanol, methanol, water mixed with ethanol, and water mixed withmethanol.

Preferably, the 1-methoxymethyl-5,5-diphenylbarbituric acid has a puritygreater than 97%. More preferably, the1-methoxymethyl-5,5-diphenylbarbituric acid has a purity greater than98%. More preferably, the 1-methoxymethyl-5,5-diphenylbarbituric acidhas a purity greater than 99%.

The present invention provides a process for preparing1-methoxymethyl-5,5-diphenylbarbituric acid by removing onemethoxymethyl group from 1,3-bis(methoxymethyl)-5,5-diphenylbarbituricacid. The present invention is further illustrated, but not limited, bythe following examples.

EXAMPLES Example 1 Preparation of 1-methoxymethyl-5,5-diphenylbarbituricacid Reaction of 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid witha Lewis acid

A reactor was charged with chlorobenzene (15 mL) under nitrogen withstirring. 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid (1.84 g, 5mmol) was added to the reactor, and the mixture was stirred for 10minutes. The mixture was then heated to 55-60° C. and stirred foranother 10 minutes. Aluminum chloride (AlCl₃, 0.66 g, 5 mmol, 1equivalent) was added, and the mixture was stirred for 10 minutes atabout 60° C. The mixture was then heated to 100-110 C. and stirred foranother 10 minutes. The mixture was then cooled to about 60° C. and thenitrogen flow was stopped.

Isolation of 1-methoxvmethyl-5.5-diphenylbarbituric acid

A cold solution of hydrochloric acid (32%, 0.5 mL) in deionized water(30 mL) was added to the mixture, and the resulting mixture was stirredat 5° C. for about 30 minutes. The resulting suspension was filtered,and the precipitate was washed with cold chlorobenzene (2 mL). Thefiltrates were combined, and the chlorobenzene (lower) phase wasseparated. A majority of the chlorobenzene phase was then removed byevaporation.

Ethyl acetate (10 mL) was added to the resulting concentrate, and thesolution was extracted with 0.5 N sodium hydroxide (15 mL), whilemaintaining the solution at a temperature of 20° C. or lower. The phaseswere separated, and the ethyl acetate phase was washed with colddeionized water (15 mL). The phases were again separated, and theaqueous phases were combined. The combined aqueous phases were acidifiedwith hydrochloric acid (32%, 1 mL), while maintaining the mixture at atemperature below 20° C. and the mixture was stirred for 30 minutes. Theresulting suspension was then filtered, and the precipitate was washedwith deionized water (5 mL) to yield crude1-methoxymethyl-5,5-diphenylbarbituric acid (0.87 g).

Purification of 1-methoxymethyl-5,5-diphenylbarbituric acid

Ethanol (95%, 4.5 mL) was added to the crude1-methoxymethyl-5,5-diphenylbarbituric acid. The resulting mixture washeated to 60° C. and stirred for about 30 minutes, then cooled to roomtemperature and stirred for an additional 30 minutes. The resultingsuspension was filtered, and the precipitate was washed with ethanol(95%, 1 mL). The wet precipitate was dried in a vacuum oven at 60° C.for about 10 hours to provide 1-methoxymethyl-5,5-diphenylbarbituricacid. Yield: 26%; Purity: 98%

Example 2 Preparation of 1-methoxymethyl-5,5-diphenylbarbituric acidReaction of 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid with aLewis acid

1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid (1.04 kg, 2.82 mol)was suspended in chlorobenzene (8 L). The suspension was heated to55-60° C. and stirred under nitrogen during 10 minutes. Aluminumchloride (AlCl₃, 0.23 kg, 1.73 mol, 0.6 equivalent) was then added inportions, and the suspension mixed at 55-60° C. for 30 minutes. Thereaction mixture was then heated to 105° C. and stirred for 2-3 hoursuntil complete dissolution was observed.

Isolation of 1-methoxyethyl-5,5-diphenylbarbituric acid

The reaction mixture was then cooled to 70-80° C. and water (4 L) wasadded. The resulting mixture was cooled to 10° C. and stirred for 10-21hours. The resulting suspension was filtered, and the filtrate wasseparated into organic and aqueous phases. To the organic phase wasadded an aqueous solution of sodium hydroxide (50%, 0.23 kg), water (1.2L), and methanol (5.7 L), the addition being performed at a temperatureof 10° C. or lower. The two-phase mixture was then stirred for about 10minutes, and the phases were separated.

To the aqueous phase was added hydrochloric acid (32%, 0.32 L), whilekeeping the temperature below 20° C. The methanol was then distilled outof the mixture at reduced pressure, and the resulting precipitate wasfiltered and dried to provide a crude product (0.366 kg) containing1-methoxymethyl-5,5-diphenylbarbituric acid (78% w/w),5,5-diphenylbarbituric acid (6% w/w), and1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid (2.7% w/w).

Purification of 1-methoxvmethyl-5,5-diphenvlbarbituric acid

The crude product was combined with a mixture of methanol:water (1:1(v/v), 10 L). The resulting mixture was heated to 70-75° C. and stirredfor about 90 minutes, then cooled to room temperature and stirred for 30minutes. The resulting precipitate was then filtered, washed withmethanol:water (1:1 (v/v), about 1 L), and dried in a vacuum oven (60°C. about 10 hours) to provide a purified product (0.254 kg) containing1-methoxymethyl-5,5-diphenylbarbituric acid (82% w/w),5,5-diphenylbarbituric acid (4.2% w/w), and1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid (1.7% w/w). In someexperiments, this product was further recrystallized from toluene andthen methanol to obtain 1-methoxymethyl-5,5-diphenylbarbituric acidhaving a purity of >99%.

All references cited herein are incorporated by reference. Theembodiments illustrated and discussed in this specification are intendedonly to teach those skilled in the art to make and use the invention.Nothing in this specification should be considered as limiting the scopeof the present invention. Modifications and variations of theabove-described embodiments of the invention are possible withoutdeparting from the invention, as appreciated by those skilled in the artin light of the present teachings.

1. A process for preparing 1-methoxymethyl-5,5-diphenylbarbituric acidcomprising the steps of: (a) reacting1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid with about 0.2 toabout 2 equivalents of a Lewis acid selected from the group consistingof aluminum chloride, boron trifluoride diethyl etherate, borontribromide, and mixtures thereof, at a temperature of about 70° C. toabout 130° C. for about one to about five hours to form1-methoxymethyl-5,5-diphenylbarbituric acid; and (b) isolating the1-methoxymethyl-5,5-diphenylbarbituric acid.
 2. The process of claim 1,wherein the Lewis acid is aluminum chloride.
 3. The process of claim 1,wherein step (a) is performed in an aromatic solvent.
 4. The process ofclaim 3, wherein the aromatic solvent is selected from the groupconsisting of chlorobenzene, bromobenzene, nitrobenzene,dichlorobenzene, o-nitrotoluene, anisole, and mixtures thereof.
 5. Theprocess of claim 3, wherein the aromatic solvent is chlorobenzene. 6.The process of claim 1, wherein the1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid is reacted with about0.4 to about 1 equivalent of the Lewis acid.
 7. The process of claim 1,wherein the 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid isreacted with about 0.6 equivalent of the Lewis acid.
 8. The process ofclaim 1, wherein step (a) is performed at a temperature of about 80° C.to about 120° C.
 9. The process of claim 1, wherein step (a) isperformed at a temperature of about 90° C. to about 110° C.
 10. Theprocess of claim 1, wherein step (a) is performed for about two hours.11. The process of claim 1, wherein the1-methoxymethyl-5,5-diphenylbarbituric acid is produced as a singlebatch of at least about 500 grams.
 12. The process of claim 1, whereinstep (b) further comprises the steps of: a′) extracting the1-methoxymethyl-5,5-diphenylbarbituric acid into a basic aqueoussolution; b′) acidifying the basic aqueous solution to precipitate theextracted 1-methoxymethyl-5,5-diphenylbarbituric acid; and c′)collecting the precipitated 1-methoxymethyl-5,5-diphenylbarbituric acid.13. The process of claim 12, wherein the basic aqueous solution is asodium hydroxide solution.
 14. The process of claim 3, wherein step (b)further comprises the steps of: a′) combining the aromatic solvent withwater to form a precipitate; b′) separating the aromatic solvent fromthe water and the precipitate; c′) extracting the1-methoxymethyl-5,5-diphenylbarbituric acid from the aromatic solventinto a basic aqueous solution; d′) acidifying the basic aqueous solutionto precipitate the extracted 1-methoxymethyl-5,5-diphenylbarbituricacid; and e′) collecting the precipitated1-methoxymethyl-5,5-diphenylbarbituric acid.
 15. The process of claim14, wherein the basic aqueous solution is a sodium hydroxide solution.16. The process of claim 3, wherein step (b) further comprises the stepsof: a′) combining the aromatic solvent with an acidic aqueous solutionto form a precipitate; b′) separating the aromatic solvent from theacidic aqueous solution and the precipitate; c′) evaporating thearomatic solvent to form a concentrate; d′) dissolving the concentratein a non-aromatic organic solvent; e′) extracting the1-methoxymethyl-5,5-diphenylbarbituric acid from the non-aromaticorganic solvent into a basic aqueous solution; f′) acidifying the basicaqueous solution to precipitate the extracted1-methoxymethyl-5,5-diphenylbarbituric acid; and g′) collecting theprecipitated 1-methoxymethyl-5,5-diphenylbarbituric acid.
 17. Theprocess of claim 16, wherein the basic aqueous solution is a sodiumhydroxide solution.
 18. The process of claim 16, wherein thenon-aromatic organic solvent is selected from the group consisting ofethyl acetate, diethyl ether, methylene chloride, and mixtures thereof.19. The process of claim 16, wherein the non-aromatic organic solvent isethyl acetate.
 20. The process of claim 1, further comprising the stepof purifying the isolated 1-methoxymethyl-5,5-diphenylbarbituric acid.21. The process of claim 20, wherein the purifying step is performed bycrystallization from a solvent.
 22. The process of claim 21, wherein thesolvent is at least one solvent selected from the group consisting oftoluene, tert-butyl methyl ether, ethanol, methanol, water mixed withethanol, and water mixed with methanol.
 23. The process of claim 20,wherein the 1-methoxymethyl-5,5-diphenylbarbituric acid has a puritygreater than 99%.